Basically substituted 1(2H)-phthalazinone derivatives

ABSTRACT

The present invention relates to new pharmacologically valuable basically substituted 1(2H)-phthalazinone derivatives having excellent coronary dilator properties and which have the general formula   AND THEIR PHARMACEUTICALLY ACCEPTABLE ACID ADDITION SALTS, WHEREIN R&#39;&#39; stands for a radical selected from the group consisting of secondary aliphatic, cycloaliphatic and araliphatic amines having 2 to 10 carbon atoms and 5,6 or 7-membered heterocyclic nitrogen bases, which contain in addition to the nitrogen atom a corresponding number of methylene groups as well as, optionally, an additional member selected from the group consisting of a nitrogen, an oxygen and a sulfur atom, said radical being bound via a nitrogen atom, R1 stands for a member selected from the group consisting of a hydrogen atom and alkoxy radical having 1 to 4 carbon atoms, which radical may be in the 6,7, 7,8 or 5,6,7 position of the phthalazine nucleus, R2 is a member selected from the group consisting of hydrogen, alkyl and aralkyl, R3 stands for alkoxy groups having 1 to 4 carbon atoms M IS AN INTEGER SELECTED FROM 1, 2 AND 3 AND N IS AN INTEGER SELECTED FROM 2 AND 3; AND TO PROCESSES FOR PRODUCING SAID DERIVATIVES.

Stachel, deceased et al.

July 6, 1975 BASICALLY SUBSTITUTED 1(2H)-PHTHALAZINONE DERIVATIVES [75] lnventors: Adolf Stachel, deceased, late of Frankfurt am Main; by Lydia Katharina Stachel, heiress, Offenbach; Rudi Beyerle, Bruchkobel; Wilhelm Kunze, Bad Homburg v.d.H.; Rolf- Eberhard Nitz, Bergen-Enkheim; Josef Scholtholt, Frankfurt, all of Germany [73] Assignee: Cassella Farbwerke Mainkur Akt.,

1 Frankfurt am Main-Fechenheim,

Germany [22] Filed: May 11, 1973 [21] Appl. No.: 359,405

Related US. Application Data [62] Division of Ser. No 237,957, March 24, 1972, Pat.

[30] Foreign Application Priority Data Mar. 27,1971 Germany 2114884 [52] US. Cl..... ..260/247.2 A; 260/243 B; 260/247.2 B; 260/250 P; 424/246; 424/248; 424/250 [51] Int. Cl? C07D 51/06 [58] Field of Search... 260/247.2 B, 250 P, 247.2 A, 260/243 B [56] References Cited OTHER PUBLICATIONS Kost, An. et all, Khim. Ferm. Zh 1(3), 43-47 (1967).

Primary ExaminerAnton H. Sutto Assistant ExaminerPaul J. Killos Attorney, Agent, or Firm-Francis M. Crawford [57] ABSTRACT The present invention relates to new pharmacologically valuable basically substituted 1(2l-l)- phthalazinone derivatives having excellent coronary dilator properties and which have the general formula [2 e g RIF Q6 2 2 7 ll 0 0 l and their pharmaceutically acceptable acid addition salts,

wherein R stands for a radical selected from the group consisting of secondary aliphatic, cycloaliphatic and araliphatic amines having 2 to 10 carbon atoms and 5,6 or 7-membered heterocyclic nitrogen bases, which contain in addition to the nitrogen atom a corresponding number of methylene groups as well as, optionally, an additional member selected from the group consisting of a nitrogen, an oxygen and a sulfur atom, said radical being bound via a nitrogen atom,

1R stands for a member selected from the group consisting of a hydrogen atom and alkoxy radical having 1 to 4 carbon atoms, which radical may be in the 6,7, 7,8 or 5,6,7 position of the phthalazine nucleus,

R is a member selected from the group consisting of hydrogen, alkyl and aralkyl,

R stands for alkoxy groups having 1 to 4 carbon atoms in is an integer selected from 1, 2 and 3 and n is an integer selected from 2 and 3; and to processes for producing said derivatives.

6 Claims, No Drawings EEASHCALLY SUBSTETUTED i(221i)-lFli-l'llZdi1 rLAZlll l @NE DEREVATHV The present application is a division of our Ser. No. 237,957, filed Mar. 24, 1972, now US. Pat. No. 3,845,052.

the present invention relates to new, pharmacologically valuable, basically substituted 1 (2l-l) phthalazinone derivatives having the general formula LI U ah- 1 1, a. r a r i it Q tl CH CIEH (M R and their pharmaceutically acceptable acid salts,

wherein R stands for a secondary aliphatic, cycloaliphatic or araliphatic amine radical having 2 to carbon atoms or the radical of a 5, 6 or 7-membered saturated heterocyclic amine, optionally containing an additional N, O or 3 hetero atom,

R represents hydrogen or an alkoxy group having 1 to 4 carbon atoms,

R represents hydrogen or an alkyl or aralkyl group,

R represents an alkoxy group having 1 to 4- carbon atoms,

m is 1,2 or 3 and n is 2 or 3, the groups R being attached if present to the phthalazine nucleus in the 6 and 7, 7 and 8 or 5,

t5 and 7 positions.

The secondary amine radical R may be derived from an aliphatic mono or diamine, such as a dialkylamine, alltylalkenylarnine, alkylenediamine, hydroxyalkylamine 0r alkoxyalkylarnine.

Suitable amines are for instance: dimethylamine, diethylamine, N-allyl-N-methylamine, l I,N-diethyl-N- methylethylenediamine, N,N-diethyl-N methylpropylenediamine, i l-methylethanolarnine, N- methylpropanolamine, N-isopropylethanolamine, N- butylethanolamine, l I-benzylethanolamine, N-methyl- N-(y-methoxypropyhamine or N-methyl-N-(y-ethoxypropyl)arnine.

@ycloaliphatic amines Mmethylcyclopropylamine, mine Araliphatic amines may be, for instance, phenalkylalkylamines such as N-benzyl-N-methylamine or N-phenethyLN-methylamine.

Radicals of heterocylic amines may be, for instance, pyrrolidino, morpholino, thiomorpholino, piperidino, N-methylpiperazino, N-phenylpiperazino, 4-(,8- hydroxyethyl)piperazino( 1). N-( y-hydroxypropyl piperazino, hexarnethyleneimino radicals.

The l(2l l)-phthalazinone derivatives of the present invention are obtained by acylating, optionally in the presence of an acid-binding agent, l(2l-l)- phthalazinones of the general formula may be, for instance, N-methylcyclohexyla i I l n N u CH (liil-l w GH E.

wherein R and 1R have the meanings given above, and R is either defined as R above or, where R would contain an acyloxy radical of the general formula R may represent the radical of the corresponding hydroxy compound in which the acyloxy group is replaced by a hydroxy group, with an alkoxy benzoic acid of the general formula GOOH it (It I l Kt /N u CH Q GHQOHWH H which is substituted in the 2-position by a 'y-halogeno-Bhydroxypropyl radical, or the corresponding epoxy compound, with a secondary amine of the general formula Rll'l, or

b, by reacting a l(2l'l)-phthalazinone of the general formula 2 I QXN l i e Vii G a with a y-halogeno-B-hydroxypropylamine of the general formula c. by cyclizing an ortho-acyl benzoic acid of the general formula COOK with a y-amino-B-hydroxy-propylhydrazine of the general formula blood, was carried out on dogs according to the methods described by, W.K.A. Schaper and'his co-workers (see W.K.A. SCHAPER, R. XHONNEUX, and J.M. BOGAARD fUber die kontinuierliche Messung des Sauerstoffdruckes in venosen Coronarblut (Naunyn- Schmiede'bergs Arch. exp. Path. u. Pharmak. 245, 383-389 (1963). The test preparations were applied intravenously to'narcotized and spontaneously breathing animals. Under these test conditions, dilation of the coronary arteries caused by the test substances along with an increase in the coronary blood flow led to an increase in the oxygen tension in the coronary veinous blood. This oxygen tension was measured polarographically by means of a platinum electrode of the Gleichmann-Lubbers type (see U. GLEICHMANN and D.W. LUEBBERS Die Messung des Sauerstoffdruckes in Gasen und Flussigkeiten mit der Platin-Elektrode unter besonderer Berucksichtigung der Messung im Blut, Pflugers Arch. 271, 431-455 (1960). The heart rate was continuously measured by electronic methods from the systolicpeaks of the arterial blood pressure. The arterial blood pressure was measured in the known manner in the femoral artery with the aid of an electromanometer of the Statham strain-gauge type.

The following table gives the results of the pharmacological investigations which were carried out. The preparations were tested in the form of their respective hydrochlorides.

g./kg.

mouse Dosage Preparation mg./ kg. w.

Maximal increase in oxygen tension in the coronary veinous blood Maximal change in blood pressure (systolic/ diastolic) in minutes Maximal change in heart rate in minutes in in minutes in 2-[y-pyrrolidino43- (3 .4,5-trimethoxybenzoxy )-propyl 1- 5.6,7-trimethoxyl (2H phthalazinone 2-[7-diethylamino-fl- (3,4,5-trimethoxybenzoxy)-propyll- 5,6.7-trimethoxyl (2H phthalazinone Z-[y-(N-methyl-N- methoxypropyl-amino ,B-( 3,4.5-trimethoxybenzoxy )-propyl 5,6,7-trimethoxy- 1 (2H phthalazinone 2-[-y-morpholino-B- (3.4,5-trimethoxybenzoxy)-propyl]- 5,6,7-trimethoxyl (2H phthalazinone l( 2H )-phthalazinone 2-[ ymorpholino-B- 3,5-diethoxy-4-nbutoxy-benzoxy propyl ]-5,6,7-trimethoxyl (2H phthalazinone 2-['y-(4'fl-3.4,5- trimethoxybenzoxyethyl-piperazinol l '1)- /3-( 3,4,5-trimethoxybenzoxy)-propyl]-5,6,7- trimethoxy-l (2H phthalazinone 3,4.S-trimethoxy' benzoxy )-propyl-5 ,6,7-

trimethoxy-l 2H phthalazinone Continued Preparation LD 50 Dosage Maximal increase Maximal change Maximal change g./l\'g. mg./kg. in oxygen tension in heart rate in blood pressure mouse i.v. in the coronary (syglolic/ i.v. veinous blood diastolic) in in minutes in in minutes in in minutes 2[y-(4'-methy|- piperazino[ I l )-B 012 0,1 +41 +7 5 (3.4.5-trimethoxybenzoxy)-propyl]- 5.6.7-trimethoxy-1(2H)- phthalazinone 2-[y-(N-methyl-N- benzyl-amino)-fi (3.4.5-trimethoxy- 0,15 0.05 +83 10/5 20 benzoxy)-propyl]- 5,6.7-trimethoXy-1(2H)- phthalazinone 2-[ y(perhydro-azepinyl- [1])/3-(3.4.5-tn'methoxybenzoxy)-propyl]- 0.1 +37 5.6,7-trimethoxy-1(2H)- phthalazinone Z-Iy-piperidino-B- (3,4.5-trimethoxybenzoxy)-propyll- 0,1 0,1 +100 +22 55 -9/23 55 5.6,7-trimethoxy-l- (2H)-phthalazinone comparative substance:

3-(y-diethylamino-/3- 2,0 +1 18 hydroxy-propyl)-4- methyl-7-ethoxy-carbonylmethoxy-coumarine according to French Patent 5019 BSM The following examples are given for the purpose of a better understanding of the nature and the objects of this invention. The temperatures are given in degrees propyl)5,6,7-trimethoxyl (2H)-phthalazinome are dissolved in 400 c.c. chloroform and admixed with 1 1.1 g. (0.1 1 mol) triethylamine. A solution consisting of 25.3 g. (0.11 mol) 3,4,5-trimethoxybenzoyl chloride in c.c. chloroform is then added dropwise while stirring for 30 minutes at room temperature. Stirring is continued for one hour at room temperature. The reaction 6 mixture is then heated to the boil and stirred again for 8 hours under reflux. After cooling down, it is evaporated to dryness in vacuo. The residue is dissolved with stirring in dilute hydrochloric acid and the solution thus 65 obtained is filtered so as to become limpid. The aqueous hydrochloric acid solution is rendered alkaline by the introduction of solid potassium carbonate and the separating reaction product is dissolved in ethyl acetate. After drying over potassium carbonate. one ob- 0 lized tains by introducing gaseous hydrogen chloride into the ethyl acetate solution the 2-[y-morpholine-fi-(3,4,5- trimethoxybenzoxy)-propyl]-5,6,7-trimethoxy-l (2H phthalazinone hydrochloride in the form of colorless crystals melting at 194- 196.

Yield: 48 g. 78.6 of the theoretical). b. The 2-(' morpholino-B-hydroxy-propyl)-5,6,7-trimethoxyl(2l-l)-phthalazinone required above as a starting compound may be prepared as follows:

23.6 g (0.1 mol) 5,6,7trimethoxy-l(2l-l)- phthalazinone are introduced while stirring at room temperature into a solution consisting of 7 g (0.1 mol) potassium methylate in c.c. methanol. The reaction mixture is evaporated to dryness in vacuo and the remaining potassium salt is suspended in 300 c.c. anhydrous toluene. A solution consisting of 19.8 g (0.11 mol) N-(y-chloro-B-hydroxypropyl)-morpholine in 40 c.c. anhydrous dimethylsulfoxide is then added dropwise and stirring is continued overnight at 80. After cooling, the reaction mixture is triturated with water and the toluene layer is separated. The toluene phase is extracted several times with dilute hydrochloric acid. The combined hydrochloric acid solutions are filtered till clear and rendered alkaline by the addition of potassium carbonate. The base layer which separates is then dissolved in methylene chloride. The residue obtained after concentrating the methylene chloride is recrystalfrom ethyl acetate. 2(y-morpholinoB- hydroxypropyl)-5,6,7-trimethoxy- 1 (211-1)- phthalazinone is obtained in the form of colorless needles melting at 108109.

Yield: 30 g 79% of the theoretical).

c. The same intermediate may also be prepared as follows: 24 g (0.1 mol) 3,4,5-trimethoxy-phthalaldehydic acid are suspended in 300 c.c. water and admixed with 17.5 g (0.1 mol) y-morpholino-B-hydroxy-propyl-hydrazine.

3,894,015 7 8. The reaction mixture is then heated to boiling point thoxy-l(2H)-phthalazinone, with N-B-hydroxethyland stirred for 2 hours at 100; After cooling, the rac l *p'iperazine, in known manner. l tion product is filtered off by suction, washed with l The .2-( 2,3-epoxypropyl)-5,6,7-trimethoxy-l(2H)- water and dried in vacuo. l T ph-thalazinone required as intermediate is obtained by Yield: 28 g 73.8% of'the'theoretical). m.p.: 108 I -:reacting 5;6,-7-trimeth"oxy-l(2H)-phthalazinone with *1, epi'chlorohydrin as follows;

EXAMPLEz j 'i (011 mol) 5,6,7-trirnethox'y-l(2H)- .phthala zino ne are dissolved in 100 cc dimethylsulf- H l CH 0 j l oxide'a nd 1 1.2 g (0.1 mol) potassium tert. butylate are 3 m i added. The reaction mixture is stirred for 2 hours at 30 l 3.33 p-03 35 and admixed with 30 g. (0.324 mol) epichlorohyv 2 I 2 2 CH 0 g drin. After l2 hours stirring at room temperature, it is poured into 800 0.0. water and extracted'several times .5 with ethyl acetate. The combined ethyl acetate extracts are washed first with dilute sodium hydroxide solution OCH and then with water. After drying, the organic phase is 3 3 3 concentrated in vacuo. The residue is recrystallized from petroleum ether. 2-(2,3'-epoxypropyl)r5',6;7- trimethoxy-l(2H)-phthalazinone is obtained -in -the CH -0-C0- @0033 form of colorless crystals melting at l07'l08, yield: OCH 21 g 72% of the theoretical).

EXAMPLE 3 a. Starting compounds of the following general for- 25 mula are prepared by methods analogous to those described in paragraphs (b) and (c) of Examples 1 and 2,

R R and R being as defined in the table:

General formula:

42.2 g. (0.1mol)2-['y-(4-B-hydroxyethylpiperazinol l-] B-hydroxy-propyll-S ,6,7-trimethoxy- 1 (2H phthalazinone are dissolved in 300 c.c. anhydrous chloroform and admixed with 30.3 g. (0.3 mol) 3,4,5- trimethoxybenzoyl chloride in 200 0.0. anhydrous chloroform is then added dropwise while stirring at room temperature and stirring is continued for another 2 hours at room temperature. The reaction mixture is then heated to be boild and stirring is continued for another 10 hours under reflux. After cooling down, the reaction mixtureis concentrated-in vacuo and the-residue is dissolved in dilute hydrochloric acid and filtered -f" so as to become limpid. The aqueous hydrochloric acid 9H solution is then rendered alkaline by the addition of po I tassium' carbonate and the separating reaction product iln 2 P- is dissolved in ethyl acetate.. After drying 'ov'er p'otassium carbonate one obtains by introducing-gaseous hy- 40 H H -N I 0 108 drogen chloride the 2-['y-(4'-B-3,4,5-trimethoxyben- 1 v zoxyethyl-piperazinofl]) -B-(3,4,5-trimeth0xy- H -CH 120 pthalazinone dihydrochloride in the form of colorless 3 2 N(2H5)z Y needles melting at 190.-

.i)1- oily phthalazinone required as starting material 'may be pre- H o pared as follows: 7 l '50 H T Q 3 58 29.2 g. (0,] mol) 2-(2,3'-epoxypropyl) 5;6,7-trirnethoxy-l(2H) phthalazinone 'and '39" (0.3 "mol) N-B-hydroxyethyl-piperazine are dissolved in 250cc. 1 f tg 120 alcohol and then stirred for 12 hoursunder refluxfThe l i limpid reaction solution is freed in vacuo from the sol ventand the excess N-B hydroxyethyl-piperazinej The residue is recrystallized from ethyl acetate. 2-["y-(4-B- 123 hydroxyethyl-pipera'zinoll'])-B-hydroxypropyl]5',6,7 trirrieth0xy-l(2H)-phthalaiinone"is ob t l H a tained iri'the of colorless crystals melting at 1 11 Yield; 32 76% oftlioiliooio't'iool g i c. The same productis al" obltai'n ejdb" reactifngt2 ,..:.7 i l (3'-chloro-2-hydroxy-p ropyl) SLiSj-tfimethoxy- Analogously to thepr 'escripti'on givenin para liof Exl(2H)-phthalazin6ne;sprepared. lby:.-addit-ion: of .hydroamplessl-an'qi2thejfollowing compounds of the present gen chloride to 2-(2,3-epoxypropyl)-5,6, trir'neinvention are prepared-from. the abovejnitialproducts:

What is claimed is: l. Basically substituted l(2lhl)-phthalazinone derivatives having the general formula and their pharmaceutically acceptable acid addition salts,

wherein 1'? stands for a radical selected from the group consisting 0116 or 7membered heterocyclic nitrogen bases, which contain in addition to the nitrogen atom a corresponding number of methylene groups as well as, optionally, an additional member selected from the group consisting of a nitrogen, an oxygen and a sulfur atom. said radical being bound via a nitrogen atom,

R, stands for a member selected from the group consisting of a hydrogen atom and an alkoxy radical having 1 to 4 carbon atoms, which radical may be in the 6,7 7.8 or 536,7 position of the phthalazine nucleus,

a, 2-[y-morpholino-B( 3 ,4,5-triethoxy-benzoxy propyl]-5,6,7-trirnethoxy-1(2H)-phthalazinone and pharmaceutically acceptable acid addition salts thereof.

4. 2-[y-morpholiino-,B-(3,5-diethoxy-4-n-butoxybenzoxy)-propyl]-5 ,6,7-trirnethoxy- 1 (2H)- phthalazinone and pharmaceutically acceptable acid addition salts thereof.

5. 2-[y-piperidinoB( 3 ,4,5-trimethoxy-benzoxy propyl]-5,6,7-trimethoxy-l-(2H)-phthalazinone and pharmaceutically acceptable acid addition salts thereof.

6. 2-['y-(4-,B-3,4,5-trirnethoxybenzoxy-ethylpiperazino [l]-,8-(3,4,5-trimethoxy-benzoxy)-pr0pyl]- 5,6,7-trimethoxy-l(2ll-l)-phthalazinone and pharmaceutically acceptable acid addition salts thereof. 

1. BASICALLY SUBSTITUTED 1(2H)-PHTHALAZINONE DERIVATIEVES HAVING THE GENERAL FORMULA
 2. Basically substituted 1(2H)-phthalazinone derivatives as claimed in claim 1, wherein R'' is a radical selected from the group consisting of morpholino, piperidino, pyrrolidino, hexahydroazepino, N-methyl-piperazino, thiomorpholino, N-methyl-N-piperidino-propylamino and N-(3,4,5-trimethoxybenzoxy-ethyl)-piperazino said radical containing not more than 10 carbon atoms.
 3. 2-( gamma -morpholino- Beta -(3,4,5-triethoxy-benzoxy)-propyl)-5,6,7-trimethoxy-1(2H)-phthalazinone and pharmaceutically acceptable acid addition salts thereof.
 4. 2-( gamma -morpholiino- Beta -(3,5-diethoxy-4-n-butoxy-benzoxy)-propyl)-5,6,7-trimethoxy-1(2H) -phthalazinone and pharmaceutically acceptable acid addition salts thereof.
 5. 2-( gamma -piperidino- Beta -(3,4,5-trimethoxy-benzoxy)-propyl)-5,6,7-trimethoxy-1-(2H)-phthalazinone and pharmaceutically acceptable acid addition salts thereof.
 6. 2-( gamma -(4''- Beta -3,4,5-trimethoxybenzoxy-ethyl-piperazino (1'')- Beta -(3,4,5-trimethoxy-benzoxy)-propyl)-5,6,7-trimethoxy-1(2H)-phthalazinone and pharmaceutically acceptable acid addition salts thereof. 